13-lower alkyl-17-alpha-haloethynyl-17-beta - hydroxy - 4,9 - gonadien - 3 - one steroids and intermediate compounds



United States Patent 3,454,600 13-LOWER ALKYL-17-ALPHA-HALOETHYNYL-17-BETA HYDROXY 4,9 GONADIEN 3 ONE STEROIDS AND INTERMEDIATE COMPOUNDSDavid Taub, Metuchen, N.J., assignor to Merck & Co., Inc., Rahway, N.J.,a corporation of New Jersey No Drawing. Filed Aug. 13, 1965, Ser. No.479,627 Int. Cl. C07d 7/20; C07c 171/00; A61k 27/00 US. Cl. 260345.2 15Claims ABSTRACT OF THE DISCLOSURE The invention disclosed herein relatesto novel processes for the preparation of compounds which are orally andparenterally active progestational agents and to novel intermediatecompounds which are useful in the preparation of compounds havingutility as orally and parenterally active progestational agents. Moreparticularly, this invention relates to novel processes for thepreparation of 13- lower alkylHot-haloethynyl-l7,8-hydroXy-4,9-gonadien- 3-one steroids, which arevaluable as progestational agents and are useful in the regulation ofthe estrus cycle in domestic animals, and to the intermediate compoundsin the processes for the preparation of such 13-1ower alkyl- 170ahaloethynyl 17,8 hydroxy 4,9 gonadien 3- one steroids. In this process,2-methyl-5-oxo-4H-5,6,7,8- tetrahydrochromene is reacted with a vinylmagnesium halide to form Z-methyl-S-vinyl--hydroxy-4H-5,6,7,8-tetrahydrochromene which is then reacted with a 2-loweralkyl-cyclopentane-1,3-dione to produce 3-methyl-13- lower alkyl 8,14seco 4 oxagona 2,5(),9(11)- triene-14,17-dione; the latter compound istreated with a strong acid thereby closing the C-ring to produce 3-methyl 13 lower alkyl 4 oxagona 2,5 (10),8,14- tetraene-17-one whichupon reaction with an aqueous solution of an organic acid is convertedby the opening of the A-ring to 13-lower alkyl-4,5-secogona-8,14-diene-3,5,l7-trione; the last-named compound is then reacted with hydrogen,thereby reducing the A -double bond to produce 13-loweralkyl-4,5-secog0na-8-ene-3,5,17-trione which is then reacted with analkali metal alkoxide to close the A-ring and form the corresponding13-lower alkyl-4,9-gonadien-3,l7-dione. The latter compound is thenreacted with a haloethynylation agent to produce 13- lower alkyl 17ahaloethynyl 17B hydroxy 4,9- gonadien-3-one.

The 13-lower alkyl-l7arhaloethynyl-17B-hydroxy-4,9- gonadien-3-onesteroids have been shown to have utility as progestational agents andbecause of this property they may be used to regulate the estrus cyclein domestic animals and in cases of menstrual disturbances may be usedto reestablish the normal relationships between the anteriorpituitary,ovary, and endometrium which are present in a normal estrus cycle. Theymay also be used to synchronize the estrus cycles of a herd or colony ofdomestic animals. When used for these purposes, they may be suppliedtogether or in succession with an estrogenic hormone.

Because of their progesterone-like effects, they affect the scretion ofgonadotropins and thus act to regulate ovulation and endometrial andplacental development.

"Ice

When combined with estrogens or androgens, they reduce fertility. Theyalso have utility in correcting disorders such-as dysmenorrhea,amenorrhea, threatened abortion, endometriosis, and the like.

The novel processes of this invention, starting with2-methyl-5-oxo-4H-5,6,7,8-tetrahydro chromene, may be schematicallyrepresented by the following series of reactions wherein R is a loweralkyl substituent, preferably having not more than five carbon atoms,such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,tertiary-butyl, pentyl and isopentyl radicals:

CH =CHMgCl CHa i I i I m O H --r on, 0 on, 0

v VI

o o k /K l l l CH3 CHI tv vm 0H 0H RI cm 0 cm 0 x1 vrr R --czoo1 XII Thestarting material in the novel processes of this invention is 2-methyl-5oxo 4H-5,6,7,8-tetrahydro chromene (Compound I). The first step in theprocesses of this invention is the reaction of Compound I with a vinylmagnesium halide to provide 2-methyl-5-vinyl-5- hydroxy 4H 5,6,7,8tetrahydro chromene (Compound II). The second step is the reaction ofCompound II with 2-lower alkyl-cyclopentane-1,3-dione to provide3-methyl- 13-lower alkyl-8,14-seco-4 oxagona-2,5 10) ,9( 1 l -triene-14,1-7-dione (Compound III). The third step is the treatment of CompoundIII with a strong acid, such as hydrogen chloride, phosphoric acid,sulfuric acid, or paratoluenesulfonic acid, to close the C-ring andprovide 3- methyl-l3-lower alkyl-4-oxagona 2,5(10),'8,l4-tetraen- 17-one(Compound IV). The fourth step is the opening of the A-ring of CompoundIV by treatment with an aqueous solution of an organic acid, such asacetic acid, propionic acid, or oxalic acid, to provide 13-loweralkyl-4,5-secogona-8,l4-diene-3,5,l7-trione (Compound V). The fifth stepis the hydrogenation of the A -double bond of Compound V to providel3-lower alkyl-4, secogona-8-ene-3,5,1=7-trione (Compound VI). The sixthstep is the closure of the A-ring of Compound VI by .4 treatment with analkali metal lower alkoxide to provide 13-lower alkyl 4,9 gonadiene 3,17dione (Compound VII).

In an alternate process for the production of Compound VII, the firststep is the reduction of the l7-keto group of Compound IV to al7fl-hydroxy group by treatment of Compound -IV with a reducing agent,such as lithium aluminum hydride in a lower aliphatic ether or sodiumborohydride in a lower aliphatic alcohol, to provide 3- methyl-lB-lower=alkyl-4-oxagona-2,5(10),8,14 tetraen- 1713-01 (Compound VIH). Thesecond step is the opening of the A-ring of Compound VIII to provide13-lower alkyl-17 3-hydroxy-4,5-secogona-8,l4diene 3,5 dione (CompoundIX). This is accomplished in the same manner as opening of the A-ring ofCompound IV. The third step is the catalytic hydrogenation of the ri-double bond of Compound IX to provide 13-l0wer =alkyl-17fi-hydroxy-4,5-secogona-8-ene-3,5-dione (Compound X). The hydro genation ofCompound IX is accomplished in the same manner as the hydrogenation ofthe A -double bond of Compound V. The fourth step is the closure of theA-ring of Compound X to provide 13-1oweralkyl-l7fi-hydroxygona-4,9-dien-3-one (Compound XI). The closure of theA-ring of Compound X is accomplished in the same manner as closure ofthe A-ring of Compound VI. The fifth step is the oxidation of thel7fl-hydroxy group of Compound XI to a 17-keto group to provide CompoundVII. The oxidation is accomplished by the use of a mild oxidizing agent,such as sodium dichromate in glacial acetic acid, a mixture of chromicacid anhydride in pyridine, or a mixture of chromic acid, sulfuric acidand acetone. Compound VII, prepared by either of the two routesdescribed above, is haloethynylated to provide 13-loweralkyl-l'hx-haloethynyl-1-7;8-hydroxy-4,-9-gonadien-3 one (Compound XII).This is conveniently accomplished by the use of an equal molar amount ofhaloethyne which is preferably formed in situ by the reaction of a 1,2-dihaloethylene (preferably in cis form) and methyl lithium.

The first step in the first process for the preparation of Iii-loweralkyl-l'la-haloethynyl-l7 8-hydroxy 4,9 gonadiene-3-one steroids by thereaction of Z-methyl-S-oxo- 4H-5,6,7, 8-tetrahydro chromene (Compound I)with vinyl magnesium halide, such as vinyl magnesium bromide or vinylmagnesium chloride, to produce Z-methyl-5-vinyl=5-hydroxy-4H5,6,7,8-tetrahydro chromene (Compound II) may beconveniently accomplished by adding a solution of Compound I intetrahydrofuran and ether to a solution of the vinyl magnesium halide intetrahydrofuran, which is maintained at a temperature of about -5 C. Thetemperature of the reaction mixture is allowed to come to roomtemperature with stirring. The product is isolated by cooling thereaction mixture to below 0 C. and carefully adding saturated aqueousammonium chloride solution. The inorganic slurry is separated from theorganic layer and extracted with ether, the organic layer and the etherextract are combined, washed with aqueous potassium bicarbonatesolution, dried over anhydrous sodium sulfate, and concentrated todryness under reduced pressure. The residue is Compound II.

In the second step, the reaction of Compound II with 2-loweralkyl-cyclopentane-1,3-dione to provide 3- methy1-13-loweralky1-8,14-seco-4-oxagona 2,5(10),9 (11)-triente-14,17dione (CompoundIII) may be accomplished by refluxing a solution of Compound II and 2-lower alkyl-cyclopentane-1,3-dione in xylene and tertiary-butanol undernitrogen. In isolating the reaction product, the reaction mixture iscooled, ether is added, the resulting slurry is washed with aqueouspotassium bicarbonate solution and then with aqueous sodium chloridesolution. The organic layer is dried over magnesium sulfate andconcentrated to dryness under reduced pressure. The residue is CompoundI11.

Compound III is treated in a third step with a strong acid, such ashydrogen chloride, phosphoric acid, sulfuric acid or anhydrouspara-toluenesulfonic acid, in solution in an anhydrous aromatic solvent,such as benzene, toluene, or xylene, to close the C-ring and provide3-methyl-13-lower alkyl-4-oxagona 2,5 ),8,14 tetraen-17-one (CompoundIV). The reaction mixture is maintained at a temperature of about 60 C.under a gentle stream of nitrogen for about 30 minutes. The reactionproduct may be conveniently isolated by cooling the reaction mixture andadding benzene and water. The organic phase is then separated, washedwith dilute aqueous potassium bicarbonate solution, washed withsaturate-d sodium chloride solution, dried over magnesium sulfate, andthe solvent is removed under reduced pressure. The residue is CompoundIV.

The A-ring of Compound IV is opened by heating a solution of Compound IVin an aqueous solution of an organic acid, such as aqueous acetic acid,propionic acid or oxalic acid, for about 3 hours to provide 13-loweralkyl-4,5-secogona8,14-diene-3,5,17-trione (Compound V). In order toisolate Compound V, the solution is cooled, and concentrated underreduced pressure to near dryness. Water is added to the concentrate andthis mixture is extracted with chloroform. The chloroform extract iswashed with dilute aqueous potassium bicarbonate solution, then withsaturated aqueous sodium chloride solution, and dried over magnesiumsulfate. The solvent is removed by distillation under reduced pressure.The residue is Compound V.

The hydrogenation of Compound V to provide 13- loweralkyl-4,5-secogona-8-ene-3,5,17-trione (Compound VI) may be catalyzed bypalladium, more particularly, 5% palladium on charcoal, and is conductedat a temperature of about 25 C. and a pressure of one atmosphere ofhydrogen until one molecular equivalent of hydrogen has been absorbed.The catalyst is removed by filtration and the solvent is removed bydistillation under reduced pressure. The residue is 13-loweralkyl-4,5-secogona-8-ene- 3,5,17-trione (Compound VI).

Closure of the A-ring of Compound VI may be accomplished by refluxing asolution of Compound VI in a lower aliphatic alcohol, such as methanolor ethanol, containing an alkali metal lower alkoxide, such as sodium orpotassium methoxide, sodium or potassium ethoxide, under nitrogen forabout four hours to provide 13-lower alkyl-4,9-gonadiene-3,l7-dione(Compound VII). To isolate Compound VII, the reaction mixture is cooled,neutralized with a weak acid, such as dilute aqueous acetic acid, andconcentrated under reduced pressure to near dryness. Water is added tothe residue, the mixture is extracted with ether, the ether layer iswashed with saturated aqueous sodium chloride solution, dried overmagnesium sulfate, and the ether is removed by distillation underreduced pressure. The residue is Compound VII.

Compound VII is ethynylated by the use of an equimolar amount ofethynylating agent, such as an ethynylating agent prepared by adding asolution of methyl lithium in dry ether to chloroethylene, to provide13- lower alkyl-l7m-chloroethynyl-17,8-hydroxy 4,9 gonadien-3-one(Compound XII).

According to the alternate process of this invention for the preparationof Compound VII, Compound IV is the starting substance. The first stepin the alternate synthesis is the reduction of the 17-keto group ofCompound IV to a hydroxy group to provide 3-methyl-13-loweralkyl-4-oxagona-2,5(l0),8,14-tetraen 17B ol (Compound VIII). Thereduction may be accomplished by adding a solution of Compound IV in alower aliphatic alcohol, such as ethanol, propanol, isopropanol orbutanol, in a dropwise manner to a solution of sodium borohydride in alower aliphatic alcohol or by adding a solution of Compound IV in alower aliphatic ether to a solution of lithium aluminum hydride in alower aliphatic ether. The temperature is maintained at about 0 C.during the addition and for about 40 minutes after addition is complete.The reaction product may be isolated from the reaction mixture by addingdilute aqueous acetic acid slowly to the reaction mixture, addingsaturated aqueous sodium chloride solution, extracting with ether,washing the ether extract with dilute aqueous potassium bicarbonatesolution, drying the solution over magnesium sulfate, and removing thesolvent by distillation under reduced pressure. The residue is CompoundVIII.

Opening of the A-ring of Compound VIII to provide 13-loweralkyl-17/3-hydroxy4,5-secogona-8,14 diene 3,5-dione (Compound IX) isaccomplished in the same manner described above for the opening of theA-ring of Compound IV.

The A -double bond of Compound IX may be hydrogenated to provide13-lower alkyl-17/3-hydroxy-4,5-secogona-8-ene-3,5-dione (Compound X).Hydrogenation is accomplished in thesame manner described above withrespect to the hyrdrogenation of the A -double bond of Compound V.

Closure of the A-ring of Compound X to provide 13- loweralkyl-l7fi-hydroxy-4,9-gonadien-3-one (Compound XI) may be accomplishedin the same manner described above in connection with the closure of theA-ring of Compound VI.

The oxidation of the H s-hydroxy group of Compound XI to a keto group toprovide Compound VII may be accomplished by the use of a mild oxidizingagent, such as sodium dichromate in glacial acetic acid, a mixture ofchromic acid anhydride and pyridine, or a mixture of chromic acid,sulfuric acid and acetone. Compound VII may be conveniently isolatedfrom the reaction mixture by the addition of water to precipitateCompound VII, addition of saturated sodium chloride solution, extractionwith ether, washing the ether extract with dilute aqueous potassiumbicarbonate solution, drying the ether extract over magnesium sulfate,and finally removing the ether by distillation under reduced pressure.The residue is Compound VII.

The following examples illustrate methods of carrying out the presentinvention, but it is to be understood that these examples are given forpurposes of illustration and not of limitation.

Example 1.2-methyl-S-vinyl-5-hydroxy-4H-5,6,7,8- tetrahydro chromeneFive grams of vinyl bromide in 5 ml. of tetrahydrofuran are addeddropwise to a stirred suspension of 900 mg. of magnesium turnings and 9ml. of tetrahydrofuran which is kept under nitrogen. During the additionthe temperature is maintained at 50-60 C. The solution of Grignardreagent is cooled to 5 C. and a solution of 1.6 g. of2-methyl-5-oxo4H-5,6,7,S-tetrahydro chromene in 5 ml. of tetrahydrofuranand 15 ml. of ether is added over a period of 20 minutes. The mixture isstirred at room temperature for three hours and then cooled to -5 C.Fifteen milliliters of saturated aqueous ammonium chloride solution isadded dropwise to the cooled reaction mixture. The inorganic slurry isseparated from the organic layer and extracted with ether. The etherextract is added to the organic layer and the combined solution iswashed with dilute aqueous potassium bicarbonate solution, dried overanhydrous sodium sulfate and concentrated to dryness under reducedpressure. The residue is 2 methyl 5 vinyl 5 hydroxy 4H 5,6,7,8tetrahydro chromene.

Example 2.3,l3-dimethyl-8,14-seco-4-oxagona-2,5(l0), 9l1)-triene-14,17-dione A solution of 840 mg. ofZ-methyl-S-vinyl-S-hydroxy- 4H-5,6,7,8-tetrahydro chromene and 540 mg.of Z-methylcyclopentane-l,3-dione in 6 ml. of xylene and 3 ml. oftertiarybutanol is refluxed under nitrogen for three hours.

The reaction mixture is cooled, ether is added and the resulting slurryis washed with aqueous potassium bicarbonate solution and then withsaturated aqueous sodium chloride solution. The organic layer is driedover magnesium sulfate and concentrated to dryness under reducedpressure. The residue is 3,13-dimethyl-8,14-seco-4-oxagona-2,5(10),9(11)-triene-14,17-dione.

Example 3 .3-methyl-13-ethyl-8,l4-seco-4-oxagona-2,5 ,9 1 1 -triene-14,l7-dione A solution of 840 mg. of Z-methyl-5-vinyl-5-hydroxy-4H-5,6,7,8-tetrahydro chromene and 540 mg. of2-ethylcyclopentane-1,3-dione in 6 m1. of xylene and 3 ml. oftertiarybutanol is refluxed under nitrogen for three hours. The reactionmixture is cooled, ether is added and the resulting slurry is washedwith 5% aqueous potassium bicarbonate solution and then with saturatedaqueous sodium chloride solution. The organic layer is dried overmagnesium sulfate and concentrated to dryness under reduced pressure.The residue is 3-methyl-13-ethyl-8,14- seco-4-oxagona-2,5 10) ,9( l 1)-triene-14, l 7-dione.

Example 4.-3-rnethy1-13-isopropyl-8,14-seco-4-oxagona-2,5(10),9(11)-triene-14,l7-dione A solution of 840 mg. ofZ-methyl-S-vinyl-S-hydroxy- 4H-5,6,7,8-tetrahydro chromene and 540 mg.of 2-isopropylcyclopentane-1,3-dione in 6 m1. of xylene and 3 ml. oftertiarybutanol is refluxed under nitrogen for three hours. The reactionmixture is cooled, ether is added and the resulting slurry is washedwith 5% aqueous potassium bicarbonate solution and then with saturatedaqueous sodium chloride solution. The organic layer is dried overmagnesium sulfate and concentrated to dryness under reduced pressure.The residue is 3-methyl-l3-isopropyl- 8,l4-seco-4-oxagona-2,5(10),9(l1)-triene-l4,17-dione.

Example 5.3,13-dimethyl-4-oxagona-2,5 10),8-l4- tetraene-17-one Asolution of 30 mg. of para-toluenesulfonic acid monohydrate in 10 ml. ofbenzene is concentrated to dryness at 60 C. under nitrogen. A solutionof 560 mg. of 3,13-dimethyl-8, 14-seco-4-oxagona-2,5 10 ,9 1 1) triene-14,17-dione in 10 ml. of anhydrous benzene is added to a solution of theanhydrous para-toluenesulfonic acid, prepared as above, in 5 m1. ofanhydrous benzene. The reaction is maintained at a temperature of 60 C.under a gentle stream of nitrogen for 30 minutes. It is then cooled andml. of benzene and 20 ml. of water are added to the cooled reactionmixture. The organic phase of the reaction mixture is separated andwashed with dilute aqueous potassium bicarbonate solution and then withsaturated sodium chloride solution. The washed solution is dried overmagnesium sulfate and the solvent is removed under reduced pressure. Theresidue is 3,13-dimethyl-4-oxagona-2,5 10 ,8, l4-tetraene-1 7-one.

Example 6.-3-methyl-l3-ethyl-4-oxagona-2,5 10) ,8,14- tetraene-17-one Asolution of mg. of para-toluenesulfonic acid monohydrate in 10 ml. ofbenzene is concentrated to dryness at 60 C. under nitrogen. A solutionof 560 mg. of 3-methy1- l3-ethy1-8,l4-seco 4 oxagona 2,5(10),9(11)-triene- 14,17-dione in 10 ml. of anhydrous benzene is addedto a solution of the anhydrous para-toluenesulfonic acid, prepared asabove, in 5 ml. of anhydrous benzene. The reaction is maintained at atemperature of 60 C. under a gentle stream of nitrogen for 30 minutes.It is then cooled and 20 ml. of benzene and 20 ml. of water are added tothe cooled reaction mixture. The organic phase of the reaction mixtureis separated and washed with dilute aqueous potassium bicarbonatesolution and then saturated sodium chloride solution. The washedsolution is dried over magnesium sulfate and the solvent is removedunder reduced pressure. The residue is 3 methyl-13-ethyl-4-oxagona- 2,510) ,8,14-tetraene-17-one.

Example 7.-3-methyl-13-isopropyl-4-oxagona-2,5(10), 8,14-tetraene-17-oneA solution of 30 mg. of para-toluenesulfonic acid monohydrate in 10 ml.of benzene is concentrated to dryness at 60 C. under nitrogen. Asolution of 560 mg. of 3-methyl- 13-isopropyl 8,14seco-4-oxagona-2,5(10),9(11)-triene- 14,17-dione in 10 ml. of anhydrousbenzene is added to a solution of the anhydrous para-toluenesulfonicacid, prepared as above, in 5 ml. of anhydrous benzene. The reaction ismaintained at a temperature of 60 C. under a gentle stream of nitrogenfor 30 minutes. It is then cooled and 20 ml. of benzene and 20 ml. ofwater are added to the cooled reaction mixture. The organic phase of thereaction mixture is separated and washed with dilute aqueous potassiumbicarbonate solution and then with saturated sodium chloride solution.The washed solution is dried over magnesium sulfate and the solvent isremoved under reduced pressure. The residue is3-methyl-13-isopropyl-4-oxagona-2,5 l0) ,8, l4-tetraene-17-one.

Example 8.13-methyl-4,5-se'cogona-8, 14-diene-3,5,17-

trione A solution of 500 mg. of 3,13-dimethyl-4-oxagona- 2,5(10),8,14-tetraen-17-one in 10 ml. of 50% aqueous acetic acid is heatedto a temperature of 90-95 C. and maintained at that temperature forthree hours. The solution is cooled and concentrated to near drynessunder reduced pressure. Water and chloroform are added to theconcentrate and the chloroform layer is removed and washed with 5%aqueous potassium bicarbonate solution and then with saturated aqueoussodium chloride solution. The washed chloroform solution is dried overmagnesium sulfate and the chloroform is removed under reduced pres sure.The residue is 13-methyl-4,5-secogona-8,l4-diene' 3,5,l7-trione.

Example 9.13-ethyl-4,5-secogona-8,l4-diene-3,5,l7-

trione A solution of 500 mg. of S-methyl-l3-ethyl-4-oxagona-2,5(10),8,14-tetraen-17-one in 10 ml. of 50% aqueous acetic acid isheated to a temperature of 90-95 C. and maintained at that temperaturefor three hours. The solution is cooled and concentrated to near drynessunder reduced pressure. Water and chloroform are added to theconcentrate and the chloroform layer is removed and washed with 5%aqueous potassium bicarbonate solution and then with saturated aqueoussodium chloride solution. The washed chloroform solution is dried overmagnesium sulfate and the chloroform is removed under reduced pressure.The residue is 13 ethyl-4,5-secogona-8,l4-diene- 3,5,l7-trione.

Example 10.l 3 -isopropyl-4,5-secogona-8, l 4-diene- 3,5 17-trione Asolution of 500 mg. of3-methyl-13-isopropyl-4-oxagona-2,5(10),8,14-tetraen-l7-one in 10 ml. of50% aqueous acetic acid is heated to a temperature of 9095 C. andmaintained at that temperature for three hours. The solution is cooledand concentrated to near dryness under reduced pressure. Water andchloroform are added to the concentrate and the chloroform layer isremoved and washed With 5% aqueous potassium bicarbonate solution andthen with saturated aqueous sodium chloride solution. The washedchloroform solution is dried over magnesium sulfate and the chloroformis removed under reduced pressure. The residue is13-isopropyl-4,S-secogona-S,14-diene- 3,5,17-trione.

Example 11.l3-methyl-4,5-secogona-8-ene-3,5,l7-trione A solution of 400mg. of 13-methyl-4,5-secogona-8,l4-

25 C. and one atmosphere of hydrogen in the presence of 9 100 mg. ofpalladium on charcoal. The hydrogenation is stopped when one molecularequivalent of hydrogen is absorbed. The catalyst is removed byfiltration and the solvent is removed by distillation under reducedpressure. The residue is l3-methyl-4,5-secogona-8-ene-3,5,17-trione.

Example l2.13-ethyl-4,5-secogona-8-ene-3,5,17-trione A solution of 400mg. of l3-ethyl-4,5-secogona-8,14- diene-3,5,l7-trione in 20 ml. ofbenzene is hydrogenated at 25 C. and one atmosphere of hydrogen in thepresence of 100 mg. of 5% palladium on charcoal. The hydrogenation isstopped when one molecular equivalent of hydrogen is absorbed. Thecatalyst is removed by filtration and the solvent is removed bydistillation under reduced pressure. The residue isl3-ethyl-4,5-secogona-8-ene-3,5,l7-trione.

Example 13 .13-isopropyl-4,5-secogona-8-ene-3,5,17- trione A solution of400 mg. of 13-isopropyl-4,5-secogona- 8,l4diene-3,5,l7-trione in 20 ml.of benzene is hydrogenated at 25 C. and one atmosphere of hydrogen inthe presence of 100 mg. of 5% palladium on charcoal. The hydrogenationis stopped when one molecular equivalent of hydrogen is absorbed. Thecatalyst is removed by filtration and the solvent is removed bydistillation under reduced pressure. The residue is13-isopropyl4,5-secogona- 8-ene-3,5,l7-trione.

Example 14.--19-norandrosta-4,9-diene-3,l7-dione A solution of 200 mg.of l3-methyl-4,5-secogona-8-ene- 3,5,17-tri0ne in 20 ml. of methanolcontainin 0.4 g. of sodium methoxide is refluxed under nitrogen for fourhours. The reaction mixture is cooled, neutralized with 15% aqueousacetic acid solution and then concentrated to near dryness under reducedpressure. Water is added to the concentrated reaction mixture and theresulting mixture is extracted with ether. The ether layer is removed,washed with saturated aqueous sodium chloride solution, and dried overmagnesium sulfate. The ether is removed by distillation under reducedpressure. The residue is 19-norandrosta-4,9-diene-3,17-dione and ispurified by chromatography on magnesium silicate (Florisil).

Example 15 .l 3-ethyl-4,9-gonadiene-3 l7-dione A solution of 200 mg. of13-ethyl-4,S-secogona-S-ene- 3,5,l7-trione in 20 ml. of methanolcontaining 0.4 g. of sodium methoxide is refluxed under nitrogen forfour hours. The reaction mixture is cooled, neutralized with 15% aqueousacetic acid solution and then concentrated to near dryness under reducedpressure. Water is added to the concentrated reaction mixture and theresulting mixture is extracted with ether. The ether layer is removed,washed with saturated aqueous sodium chloride solution, and dried overmagnesium sulfate. The ether is removed by distillation under reducedpressure. The residue is 13- ethyl-4.9-gonadiene-3,17-dione and ispurified by chromatography on magnesium silicate (Florisil).

Example 16.13-isopropyl-4,9-gonadiene-3,l7-dione A solution of 200 mg.of l3-isopropyl-4,5-secogona-8- ene-3,5,17-trione in 20 ml. of methanolcontaining 0.4 g. of sodium methoxide is refluxed under nitrogen forfour hours. The reaction mixture is cooled, neutralized with 15% aqueousacetic acid solution and then concentrated to near dryness under reducedpressure. Water is added to the concentrated reaction mixture and theresulting mixture is extracted with ether. The ether layer is removed,washed with saturated aqueous sodium chloride solution, and dried overmagnesium sulfate. The ether is removed by distillation under reducedpressure. The residue is l3-isopropyl-4,9-gonadiene-3,l7-dione and ispurified by chromatography on magnesium silicate (Florisil).

Example l7.--3, l 3-dimethyl-4-oxagona-2,5( 10 ,8, 14-

tetraen-l7fl-ol A solution of 500 mg. of 3,-l3-dimethyl-4-oxagona- 2,510),8,14-tetraen-l7-one in 10 ml. of isopropanol is added dropwise to astirred solution of 350 mg. of sodium borohydride in 8 ml. ofisopropanol. The reaction mixture is maintained at 0 C. during theaddition and for 40 minutes after addition is complete. Ten millilitersof 15% aqueous acetic acid solution is added dropwise to the reactionmixture followed by the addition of saturated aqueous sodium chloridesolution. The resulting mixture is extracted with ether, the etherextract is washed with dilute aqueous potassium bicarbonate solution anddried over magnesium sulfate. The ether is removed by distillation underreduced pressure. The residue is 3,13- dimethyl-4-oxagona-2,5 l0 ,8,l4-tetraen- 17 9-01.

Example 18.-3-methyl-13-ethyl-4-oxagona-2,5( 10),8, 14-

tetraen- 175-01 A solution of 500 mg. of 3-methyl-l3-ethyl-4-oxagona-2,5(10),8,14-tetraen-l7-one in 10 ml. of isopropanol is added dropwiseto a stirred solution of 350 mg. of sodium borohydride in 8 ml. ofisopropanol. The reaction mixture is maintained at 0 C. during theaddition and for 40 minutes after addition is complete. Ten millilitersof 15% aqueous acetic acid solution is added dropwise to the reactionmixture followed by the addition of saturated aqueous sodium chloridesolution. The resulting mixture is extracted with ether, the etherextract is washed with dilute aqueous potassium bicarbonate solution anddried over magnesium sulfate. The ether is removed by distillation underreduced pressure. The residue is 3-methyl-l3- ethyl-4-oxagona-2,5( 10,8, l4-tetraen- 1 75-01.

Example 19.3-methyl-13-isopropyl-4-oxagona-2,5 10) 8,14-tetraen-17B-ol Asolution of 500 mg. of 3-met-hyl-l3-isopropyl-4-oxa--gona-2,5(10),8,l4-tetraen-l7-one in 10 ml. of isopropanol is addeddropwise to a stirred solution of 350 mg. of sodium borohydride in 8 ml.of isopropanol. The reaction mixture is maintained at 0 C. during theaddition and for 40 minutes after addition is complete. Ten millilitersof 15% aqueous acetic acid solution is added dropwise to the reactionmixture followed by the addition of saturated aqueous sodium chloridesolution. The resulting mixture is extracted with ether, the etherextract is washed with dilute aqueous potassium bicarbonate solution anddried over magnesium sulfate. The ether is removed by distillation underreduced pressure. The residue is3-methyl-13-isopropyl-4-oxagona-2,5(10),8,14-tetraen-l7-B-ol.

Example 20.--13-methyl-l7fi-hydroxy-4,5-secogona- 8,14-diene-3,5-dione Asolution of 500 mg. of 3,-13-dimethyl-4-oxagona-2,5(l0),8,l4-tetraen-l7fi-ol in 10 ml. of 50% aqueous acetic acid is heatedto a temperature of 95 C. and maintained at that temperature for threehours. The solution is cooled and concentrated to near dryness underreduced pressure. Water and chloroform are added to the concentrate andthe chloroform layer is separated and washed with 5% aqueous potassiumbicarbonate solution and then with saturated aqueous sodium chloridesolution. The washed chloroform solution is dried over magnesium S111fate and the chloroform is removed under reduced pressure. The residueis 13-rnethyl-l7,B-hydroxy-4,5-secogona- 8,14-diene-3,5-dione.

Example 21.-l 3-ethyl-17,8-hydroxy-4,5-se'cogona-8,l4-

diene-3,5-dione A solution of 500 mg. of 3-methyl-l3-ethyl-4-oxagona-2,5(10),8,14-tetraen-17fl-ol in 10 ml. of 50% aqueous acetic acid isheated to a temperature of 90-95 C. and maintained at that temperaturefor three hours. The solution is cooled and concentrated to near drynessunder reduced pressure. Water and chloroform are added to theconcentrate and the chloroform layer is separated and washed withaqueous potassium bicarbonate solution and then with saturated aqueoussodium chloride solution. The washed chloroform solution is dried overmagnesium sulfate and the chloroform is removed under reduced pressure.The residue is 13-ethyl17fl-hydroxy-4,5-secogona-S,14-diene-3,5-dione.

Example 22.13-isopropyl-17/3-hydroxy-4,5-secogona- 8, l4-diene-3,5-dioneA solution of 500 mg. of3-methyl-13-isopropyl-4-oxagona-2,5(),8,14-tetraen-l7B-ol in 10 ml. of50% aqueous acetic acid is heated to a temperature of 90-95 C. andmaintained at that temperature for three hours. The solution is cooledand concentrated to near dryness under reduced pressure. Water andchloroform are added to the concentrate and the chloroform layer isseparated and washed with 5% aqueous potassium bicarbonate solution andthen with saturated aqueous sodium chloride solution. The washedchloroform solution is dried over magnesium sulfate and the chloroformis removed under reduced pressure. The residue is13-isopropyl-l7B-hydroxy-4,5-secogona-8,14-diene-3,5-dione.

Example 23.-13-methyl-17,8-hydroxy-4,5-secogona-8- ene-3,5 dione Asolution of 400 mg. of 13-methyl-17B-hydroxy-4,5-secogona-8,14-diene-3,5-dione in 20 ml. of benzene is hydrogenated at 25C. and one atmosphere of hydrogen in the presence of 100 mg. of 5%palladium on charcoal. The hydrogenation is stopped when one molecularequivalent of hydrogen is absorbed. The catalyst is removed byfiltration and the solvent is removed by distillation under reducedpressure. The residue is13-methyl-17fihydroxy-4,5-secogona-8-ene-3,5-dione.

Example 24.13-ethyl-17fi-hydroxy-4,5-secogona-8-ene- 3,5-dione Asolution of 400 mg. of 13-ethyl-17p-hydroxy-4,5-secogona-S,14-diene-3,5-dione in 20 ml. of benzene is hydrogenated at 25C. and one atmosphere of hydrogen in the presence of 100 mg. of 5%palladium on charcoal. The hydrogenation is stopped when one molecularequivalent of hydrogen is absorbed. The catalyst is removed byfiltration and the solvent is removed by distillation under reducedpressure. The residue is 13-ethyl-17fi-hydroxy-4,5-secogona-8-ene-3,5-dione.

Example 25 .13-isopropyl-17fl-hydroxy-4,5-secogona-8- ene-3,5-dione Asolution of 400 mg. of 13-isopropyl-l7fi-hydroxy-4,5-secogona-8,14-diene-3,5-dione in 20 ml. of benzene is hydrogenated at 25C. and one atmosphere of hydrogen in the presence of 100 mg. of 5%palladium on charcoal. The hydrogenation is stopped when one molecularequivalent of hydrogen is absorbed. The catalyst is removed byfiltration and the solvent is removed by distillation under reducedpressure. The residue is13-isopropy'l-17flhydroxy-4,5-secogona-8-ene-3,S-dione.

Example 26.-1 3 -methyl-17fi-hydroxy-gona-4,9-dien-3 one A solution of200 mg. of 13-methyl-17fl-hydroxy-4,5-

secogona-8-ene-3,5-dione in 20 ml. of methanol containing 0.4 g. ofsodium methoxide is refluxed under nitrogen for fours hours. Thereaction mixture is cooled, neutralized with aqueous acetic acidsolution and then concentrated to near dryness under reduced pressure.Water is added to the concentrated reaction mixture and the resultingmixture is extracted with ether. The ether layer is removed, washed withsaturated aqueous sodium chloride solution, and dried over magnesiumsulfate. The ether is removed by distillation under reduced pressure.The residue is 13-methyl-17;3-hydroxy-gona-4,9- dien-3-one and ispurified by chromatography on magnesium silicate (Florisil).

12 Example 27.-13-ethyl-17;8-hydroxy-gona-4,9- diene-3-one A solution of200 mg. of 13-ethyl-17/3-hydroxy-4,5- secogona 8 ene 3,5 dione' in 20ml. of methanol containing 0.4 g. of sodium methoxide is refluxed undernitrogen for four hours. The reaction mixture is cooled, neutralizedwith 15 aqueous acetic acid solution ond then concentrated to neardryness under reduced pressure. Water is added to the concentratedreaction mixture and the resulting mixture is extracted with ether. Theether layer is removed, washed with saturated aqueous sodium chloridesolution, and dried over magnesium sulfate. The ether is removed bydistillation under reduced pressure. The residue is13-ethyl-17p-hydroxy-gonalfi-diene-3-one and is purified bychromatography on magnesium silicate (Florisil).

Example 28.-13-isopropyl-17fl-hydroxy-gono-4,9- diene-3-one A solutionof 200 mg. of 13-isopropyl-17fl-hydroxy- 4,5-secogona-8-ene-3,S-dione in20 ml. of methanol containing 0.4 g. of sodium methoxide is refluxedunder nitrogen for four hours. The reaction mixture is cooled,neutralized with 15 aqueous acetic acid solution and then concentratedto near dryness under reduced pressure. Water is added to theconcentrated reaction mixture and the resulting mixture is extractedwith ether. The ether layer is removed, washed with saturated aqueoussodium chloride solution, and dried over magnesium sulfate. The ether isremoved by distillation under reduced pressure. The residue is13-isopropyl-17fi-hydroxy-gono-4,9-dien-3- one and is purified bychromatography on magnesium silicate (Florisil).

Example 29.-19-norandrosta-4,9-diene-3,17-dione A solution of 2.67 g. ofchromium trioxide in 2.3 ml. of concentrated sulfuric acid is dilutedwith water to ml.

0.30 ml. of the chromic-acid-aqueous sulfuric acid reagent is added to astirred solution of 300 mg. of 13- methyl 178-hydroxy-gona-4,9-diene-3-one in 50 ml. of acetone which is kept at 10C.

Five minutes after addition is complete, 200 ml. of cold water areadded. The precipitated product is filtered, washed with water, anddried in air. Crystallization from a mixture of acetone and hexane gives19-norandrosta- 4,9-diene-3,l7-dione.

Various changes and modifications may be made in carrying out thepresent invention without departing from the spirit and scope thereof.Insofar as these changes and modifications are within the purview of theannexed claims, they are to be considered as part of our invention.

What is claimed is:

1. 2 methyl 5 vinyl 5 hydroxy 4H-5,6,7,8-tetrahydrochromene.

2. 3 methyl 13 lower alkyl-8,14-seco-4-oxagona-2,5(10),9(11)-triene-l4,-17-di0ne.

3. 3,13 dimethyl 8,14 seco-4-oxagona-2,5(10), 9 1 1)-triene-14,17-dione.

4. 3 methyl 13 lower alkyl-4-oxagona-2,5(l0), 8,14-tetraen-17-one.

5. 3,13 dimethyl 4 oxagona-2,5(10),8,14-tetraen- 17-one.

6. 13 lower alkyl 4,5-secogona-8,l4-diene-3,5,17- trrone.

7. 13 methyl 4,5 secogona 8,14 diene-3,5,-17- trione.

8. 13-lower alkyl-4,5-secogona-8-ene-3,5,17-trione.

9. 13-methyl-4,5-secogona-8-ene-3,5,17-trione.

10. 3 methyl 13 lower alkyl 4-oxagona-2,5(10), 8,14-tetraen-17B-ol.

11. 3,13 dimethyl 4 oxagona 2,5(10),8,14-tetraen-17fi-ol.

12. 13 lower alkyl 17fl-hydroxy-4,5-secogona-8,14- diene 3,5-dione.

13. 13 methyl 17/3 hydroxy 4,5-secogona-8,14- diene-3,5-dione.

3,5-dione.

15. 13 methyl 17p hydroxy-4,5-secogona-8-ene-3,5-

dione.

References Cited UNITED STATES PATENTS Pappo et a1. 260-345.2 Nomin eta1. 260586 XR Nomin et a1. 260345.2 Krakower et a1. 260-3451 Baran260-3452 XR 14 OTHER REFERENCES Smith et a1.: Experientia, v01. 20, pp.418-9 (1964). Houisman et 211.: Rev. Trav. Chim., vol. 82, pp. 898- 900(1963).

HENRY R. JILES, Primary Examiner.

JOHN M. FORD, Assistant Examiner.

US. Cl. X.R.

